B
A1ION et a!.’ in 1956 described aheredi-tary disease characterized by
pellagra-like skin rash, cereheliar ataxia, mental
de-terioration, renal aminoaciduria, and
abnor-mnal urinary excretion of indoles. This
clis-ease ilas simice been termed Hartnump disease
after the surname of the first patient. Addi-tional cases have been described in
Eng-land,2 the Netherlands,’ and Germany,t
a total of 14 cases. The present investigation
deals with two cases of Hartnump disease
diagnosed in a Norwegian family. The pur-pose of the report is to give further
informa-tion \Vitil regard to the clinical martifesta-tions, to discuss the effect of therapy, and to describe the biochemical findings.
CASE REPORTS
Case 1
HISTORY: N.A., a female child, was born
in 1947. The motiler had hyperernesis dumr-ing the \vllole pregmiancy. The patient was
delivered at term, her birth \veigilt being
4,160 gm. She was slightly cyanotic and re-ceived oxygen therapy duiring tile first houmrs.
She was bottle fed. During the first year
of life she suffered from frequent diarrhea
and vomiting and was admitted to the local
hospital tilree times in this period.
Several attacks of tonsillitis necessitated tonsillectomy at the age of 7 years.
The patient was always shy, timid, and
anxious. She had increased fatigability and
difficulty in following regular school work.
She )layed mostly and best with younger
child n.
From the first summer of her life she had
till itching rash omi areas exposed to light, mainly hands, forearms, and face, but also
on other localizations if they were exposed
to the sum. The rash umsumally started in
Feb-rumary amid lasted until October; tile rest of
the year she had no skin lesions. At the age
(Accepted for i)t11)licttion,May 15, 1962.)
ADDRESS: (Ku.) Barneklinikken, Rikshospitalet, Oslo.
29
PEDIATRICS, January 1963
Karin Halvorsen and Sverre Halvorsen
Children’s HOS1)ital (171(1 Pediatric Research Laboratory, Rik.sliospitalet, Oslo, Norwat,
of 10 and 12 years she was ilospitalized for
this ailment, and a diagmiosis of eczemiia
solare was made.
During tile summer 1958 slle had attacks of sharp pains in the right side of the chest and in the neck. Shle had these pains occa-sionahly during the following years. In time
spring of 1960 they became more severe; in addition she complained of dizziness, di-plopia, stiffness in the arms and legs, and Ofl
occasiomis she was not al)le to walk upright.
She was constipated, had nausea, and lost 3 kg of weigilt in a few months. During the
spring of 1960 her nervous symptoms
in-creased. She was more restless, cried, lost 11cr temper easily, and showed signs of
con-fusion. Several days she stayed at home,
umn-able to attend schlooi. Because of increasing
rash, nervous symptoms, and constant
head-ache, she was admitted to the Children’s Hospital in May, 1960.
PHYSICAL FINDINGS: The girl, at age 13
years was well-developed. She displayed a
pronounced dermatitis on areas exposed to
light. Tile skin was thickened and scaling,
hyperpigmented, and with wet and moist
areas, especially on the cheeks (Fig. 1). She
had ectropion of the rigilt lower lid. The
hair was dry. Interlningled with wimat was
apparently her normal hair, were hairs of different and brighter color. There was an
arcuate kyphosis of the thoracic region of
the spine. She had a divergemit squint,
di-plopia, and nystagmus. Tile deep tendon re-flexes were hyperactive, the gait was ataxic, and on Rornbergs test she had a tendency
to fall. Results of the co-ordlination tests
were dlifficult to imuterpret.
On admission she had beemi crying
con-stantly for ilours, and tile first impression of
the examniner was that she suffered from
ilysteria. During the following clay’s in
30
4 isoens
Fir.. 2. Glucose tolerance tests in Cases 1 (NA.)
and 2 (E.A.). Three hours after the ingestion of
glucose Patient E.A. had definite hypoglycemic
symptoms which were revealed following milk
intake.
Fir.. 1. Plmotograph of Patieimt 1 at the time of
first a(lnussion. Note tIme localization of time rash to
tli( areas (XIliOSc(l to liglmt.
‘as anxious, and comiiplaimiecl of cuirrents
through imer body amid a feeling of wasting
of tile l1Lml(ls. Iii time psvclmological test
ma-terial, there were several observations
sug-gesting a PsYciltic reactiomi. On a verbal
in-tell igence test (Terman- \ I errill ) she mnadie a
scare equivalent to an IQ of 82.
LABORATORY FINDINGS : The hemoglobin
comicentration was 1 1 .4 gui /1111; the
erythro-cvte sedimnentation rate, 12 mm; and the
reticuiocytes, 0. 9sf. The erythrocyte,
leumko-cvte, and! differential coumits were within
miormal range. Total I)r0t(im1s in serumn were
7.0 gni/100 1111, and eiectrophoresis was
nor-nial. Thymnol reaction was 0.02; creatinine in
serum, 0.8 miig/ 100 mnl; phosphorums in serum,
4.2 mg/10() ml; amid calcium in serum, 4.7
met/l.
Urimualysis was normal on routine tests.
Time specific gravity was 1,022.
Uroporphy-rio was miot present, amid tile excretion of
coproporplmvrin :38 ig/dav. TRP (tubular
reabsorptiomi of I)ilosI)llt)rtIs) was 80%, the
normal range beimig 85 ±T 5/. A glucose
tol-erance test was approximately normal (Fig.
2). The cerebrospinal fluid was normal.
Bac-teriological examinations of tile feces showed normal flora.
Roentgenograms of the hands, cranium, and cervical and thoracic regions of the spine were normal. An electrocardiogram did not display pathological findings.
The electroencephalograms revealed defi-nitely pathological findings in May and Jumne, 1960 (Fig. 3). There was a generalized
cerebral dysrhythmia with increased theta-delta activity imi the left parietotemporal re-gion. In September, 1960, tIle
eiectroen-Fp1.F
Fl-I3
T3T5
15-01
MAI\1A/UPVVkJ\JW
Fp2-F8
14-16
16-02
‘Soy
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Fir.. 3. Case 1. Electroencephalogram at time time
of first a(lmissiOfl, showing general dysrimythmia and increased timeta-delta activity in tIme left
THREON INC
.Y,J5E-SER INC
Fir.. 4. Case 2. Urinary amino acid chromatogram simuwing time typical I I-pattern of amino acid excretion.
Note tIme lack of proline excretion. The pattern was exactly the same in Case 1.
ce)1lalographic finclimigs were mnumch
im-proved, hut this time with increased theta
activity and some sumspiciouis sllarp vaves in
time rigllt temuuporal region. In April, 1961, the
electroencephalogram did not 5110w any
focal signs, and there was only a slight
gen-eralizeci dysrilytilmia.
CHROMATOGRAPHIC STUDIES : Ain
urn
acids.Bidiniensional paper chromatography with umse of hultanoi/acetic acid/water (4:1:5) as
the first solvent and phenol/water as the
second, revealed the typical H-pattern of
urinary amino acid excretion-just as in her
brotller (Case 2) (Fig. 4). The pattern was
tile same omi repeated chromatograms
be-fore and after initiation of treatment with
nicotimiamnide.
Ifl(IO1CS. Chromatography of urinary
in-doles witi Iisopropamioi/animiuonia/vater (20:
1:2) as time first amid i)utaflol/acetic acidl/
water as the secomud silowed during the acute pllase of the disease marked spots of
imidlican, tryptophan, indole acetic acid (IAA), inclole acetyl glutamine(IAcG1uiNH),
G
LEUCINEISOLEUC INE
Q
PHENYLALANINE TRYPTOPHAN VAL INCEI
TYROSINCand indole acryl glycine (IAcrylGly)-juist
as in 11cr brother (Fig. 5). One year after
treatment ‘as startedl, and when she was
free of symptoms, the indole excretion pat-tern was the same, hut tile spots were
de-finitely weaker.
Tryptopiian loading (50 mg/kg body
weight of 1-trvptophan) increased time
cx-cretion of indican, tryptophan, IAA, IAcGIumNH and IAcrlGly; tile increase
lasted for more than 28 hours.
Following neomycin therapy, 100 mg/kg
body weight per day, for 4 days, a
trvpto-phan loading did not increase time imicioiic
acid excretiomi. The urine collected during
the first 4 hours following time trvptophan
ingestion did not show any spot from
in-dican andi only weak spots of IAA amid
IAcGlumNH. Between 24 amid 28 imotirs
there was a faint indican spot and no spots
fromn time indolic acids, this being in miiarked
contrast to time definite spots fromii the
in-dolic acids following a tryptopiman load
0
INOICAN
I AA
avrs.L ..___ (.1.
Fir.. 5. Case 2. TIme indole
has also l)eclm time same in
I(
-a 0 . 0. 0 0. 0 TRYPTOPHAN
LI
SUTANOL.1
clmromatogram Imas been exactly time same on repeated studies. (The pattern
Case 1.) Abbreviations: IAA = inclole acetic acid; IAcrylGly = indole acryl
glycine; IAcGIuNH2 = indole acetyl glutamine.
0 Afi-B-total, A/S Farmaceutisk Industri, Oslo.
TREATMENT: The diagmiosis of Hartnup
disease wa ma(le, and time patient VaS given
a combined vitamin B preparation #{176}
intra-niuscularly for 0fl week with 66 mg
nico-tinamicle daily. Later she imaci oral
medica-tion of a similar preparmtin#{176} with 40 mg
nicotinaniidle daily.
FoLLow-up: Tile therapy resumlted in a
clear-cut effect on tile rasim. After one week
tue skin was softer and time ectropion had
imnl)rOvedl markedly. Two weeks later the
signs of (lermatitis imad completely
disap-1)etredl, leavin g some hyperpigmented spots.
The headache and pains disappeared within
one week of therapy, amid there was marked improvement in her emotional status. She had a erioi of hair loss, i)ult this was only
transitory, and afterwards time hair was softer and became darker in color.
She also became more interested in school
vork and was easier to handle at home. On
psychological retesting after 5 months of
therapy tile psycilotic reaction patterns
foumid in the first study were no longer
pres-ent. An IQ test did not show significant
dif-ference from tile first.
She imas been followed for 1% years after treatment was started, and both she and her mnotimer state that her life has completely changed. No rasim has been seen duiring
two summers of observation and no definite
photosensitivity has been oi)served. The
in-creased deep tendon reflexes have persisted, otherwise the neurological findings have been normal. On repeated psychological
testing she has shown improvement, but
there has been no significant increase in IQ.
Case 2
HISTORY: E.A., a maie child, was born
1951 at term following an uncomplicated pregnancy and normal delivery. There were no neonatal complications. He was not able
to hold his head imntil he was 1 1 months old, and started to walk at the age of 15
months.
He has always been nervoums. When 5
years old, at which time a rash started, lie
had series of spells during which he was stiff, out of contact, but still conscious. He complained of seeing strange things mov-ing around. Treatment with phenobarbital improved the symptoms. From this time on
he had several types of tics.
In the summer of 1956 when lie was 5 years old, he had an itching rash on the face, hands, and legs. Since that time lie had the rash every spring and summer, with im-provement in the fall, and no rash during tue winter. During the summer of 1959, which was sunnier than usual, lie suffered
more than before from the rash, which at this time was wet and moist. Like several other members of the family, he had
fre-qument attacks of headache.
FIr.. 6. Case 2. Photograph of the hands and legs
at time time of first admission.
well. He often Imad to stay home from school
because of llea(lache and weakness. There
were no other neurological symptoms. Tile
rasll started in March of tilat year, but was
not niore Proluuimiemit tllan in the preceding
‘ears. \Vhen tile diagnosis of Hartnup
dis-ease was mnade in the sister, he was
ad-iuiitted to the Cimildremi’s Hospital for
fur-tiier Studlies.
PHYSICAL FINDINGS: The patient was a
well-dieveloped and well-nourished
9-year-old ho’. Time skin on time hands, legs, and
forearms as dry, thickened, scaling, and
with increased pigmentation (Fig. 6). Tllere
was a distinct border toward normal skin
not eXl)Osedl to sunligimt. Less distinct
cilanges were seen in time face, and
espe-cially’ on the ears. Tue hair was of a red
color, and imitersperseci between the normal
ilairs were shorter and mnore fragile hairs of
a grey color.
Tile deep tendon reflexes were
hyperac-tive, otllerwise the physical and
neumrologi-cal findings were normal.
Time psychological tests revealed some
neurotic )itterns, \vllich were unchanged
on retesting after 5 months of therapy. IQ
was 105 first time, later 109.
LABORATORY FINDINGS: The routine
eryth-rocvte and leukocyte counts were normal;
imemuuogloI)in concentration was 13.6 gm;
and the sedimentation rate was 16 mm.
Urinalysis was normal on routine tests.
Uro-porphyrin was not present, and
copropor-1)ilyrin was excreted imi normrial amnounts.
A glucose tolerance test (Fig. 2) silowed
a nornual rise, i)ut after :3 hours time patient
lladi defimuite svmnptoiiis of iivpoglycemiuia
xvith 1)roftise sveating, d0l(i claiiiniy I ianls,
and thirst. Blood stmgar at timat timiie was 45
nig/100 ml. i’lme svniptonis disappeam-ed
rap-idly following imigestiomi of miiilk.
Two electroencepl malogramiis were normuiai.
CHROMATOGRAPHIC STUDIES : Time urimiary amino acid chromnatogramns on several
oc-casions displayed the cimaracteristic
H-pat-tern (Fig. 4). Indole chromatogramns simoweci
excess of tryptopilan, imudican, IAA,
IAcGIuNH2 and IAcrylGlv (Fig. 5).
Follow-ing tryptophan loadimig, the excretion of
imi-clican andl tile inclolic acidis was markedly
increased, and the increase lasted for more
tlman 28 hours.
TREATMENT: As 500fl as time diagnosis of
Hartnup disease was confirmedi, theraiy was
startedi vith a combinedi vitamin B
prepara-tion and a daily close of 40 mug
nicotina-mide. The rash improved rapidly following
tilerapy. Durimig the rest of the sumiimer the
photosensitivity’ of the skin was definitely
less than previoumsly. The dosage was
re-cluced to 20 mg during time winter months. During time spring and summer, 1961, lme did
not have any raslm, hut following imitemise
cx-iosure to sunligilt on time shoulders he
be-camne possibly muuore sumnl)mmrne(l timami his
playfellows. Tile headache has been mumch
less distumrbing than previously.
In the fall, 1961, lie had a period with
in-creasing nervous symiuptoms, restlessness,
tics, and periods with loss of interest in the
surroundings; at the same time he talked
loudly with himself. The symT1)tommis
im-proved following sedatives. Ami
clectroen-cephalogram at that time revealed miornial
findings.
Family History
The parents were tmnrelated. The mnotiier
was nervous. She stmffered from frequent
at-tacks of headache and had had several
faint-ing spells. The grandmother and several of
the mother’s eight siblings were nervous. An
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
13 10 8 7 3 5 5 6 4 14 14acid and indole excretion were found to be normal in the latter. An aunt had anxiety neumrosis. Shle had lichen ruber, idiosyn-cratic eczema, and photosensitive skin.
Urin-ary amino acid and indole chromnatograms
and a tryptophan loading test were normal in timis person.
The fatiier was ilealtimy. One of the
fatlmer’s 10 siblings died when 7 years old
from diabetes; time others were healthy; and so were tile grandparents. The amino acids
amid indole excretion were fotmnd to be nor-mnal in both time father and mother.
The brother, BA., born in 1949, had
never had any skin lesions. He also had fre-quent attacks of headache. He was attend-ing regular school, butt was not doing too well. On a performance test lie made a score of 92. His psychomotoric development
had been normal. The amino acid
chromato-grams were normal or showed only
moder-ate and uncharacteristic increase in the ex-cretion of amino acids. The indole chroma-tograms showed distinct spots of IAA, IAcG1uNH2, and IAcrylGly, beside indican and tryptophan-in the same pattern as his two affected siblings. This observation has
been made repeatedly, and only once the
clmromatograms showed the more usual
pat-tern of indican, tryptophan, and 5HIAA as
the only visii)le spots. A tryptophan loading
test did not reveal any pathological increase
in excretion, but urine corresponding to 5
seconds excretion only was used.
The sister, IA., born in 1954, had
de-veloped normally and had never had skin
lesions or other symptoms suggestive of
Hartnup disease. Amino acid and indole
excretion were normal.
COMMENT
The clinical manifestations of Hartnup disease vary somnevhat from case to case,
but there are some maimi symptoms, none
of wimich are essential for the diagnosis.
Table I shows the frequmemicy of time most
im-portant symnptoms ill the 14 previousiy
re-ported cases’s and in our own two cases.
The rash is tue most constant symptom. It is localized to the areas exposed to light,
where the skin is dry, scaling, hyperkerato-tic, and pigmented; it is similar to the skin lesion in pellagra. Following exposure to sunlight the rash sometimes flares up and becomes moist and wet. The skin lesion usually precedes the other symptoms and
is worse during the spring and early sum-mer months.
The neurological disturbances are next in frequency. Of these, ataxia is the most disturbing, but it is transient and usually present only during acute exacerbations of
the disease. This is also true with the
com-plaints of dizziness, diplopia, and poor
co-ordination, whereas the finding of nystag-mus, and especially increased tendon re-flexes, may be present during “silent” pe-nods. Eight patients have had “fainting at-tacks” of unknown etiology. Pains in the back, chest, abdomen, or legs are fairly common and were severe in the first case in this report. The cause of the pains and the other neurological symptoms is
un-known.
Mental disturbances are common in these patients. Most of them have emotional
la-bility; they cry and become angry easily.
They are often timid, anxious, tense, and ir-ritable. During the acute exacerbations of the disease a psychotic reaction pattern with apathy, depression, hallumcinations, and
TABLE I
THE FREQUENCY OF THE MAIN SYMI’TOMS AND SIGNS
IN TilE 16 KNOWN CASES OF HAIITNu-P DISEASE
Symptoms Case 1 Case 2
Fourteen
Previously Rejrd C’ases’8
Pellagrous skin rash
Ataxia Pains “Fainting attacks” Emotiotmal lability Psychosis Mental retardation Nystagmus
Active tendon reflexes
Pathological EEG
Aminoaciduria, “H-patterim”
confusion has been reported in three cases.
On admiiissiomi to the hospital, Patient 1
was miiarkedly depressed and had possible
lmahlucniations. In the psychological tests
she shoved somne psychotic l)atterns.
Fol-lowimig improvement in tile general
condi-tion after or l)ecause of nicotinamide
tlier-aps’, time psycllOtic reaction patterns
chisap-P” rapidi, and this was also trume with
our 1)ltieflt.
Hersov and Rodnight stated that time
psychiatric symptoms in Hartnup disease
appear to be nonspecific reactions, and that similar symnptomns are well-known
accom-paninuents of toxic conditions in ciiildhood.
Time uniformity of the psychiatric reactions,
time specific toxic metabolites vhmich most
likely exist in tile disease combined with
the lack of an imnportant vitamin, suggest
however, a direct relationship. Secondary
mental changes dume to time invalidating
symnptoms will of course influence the
reac-tion I)attems.
1mmtileir original report Baron et al.1
de-scribed a progressive mental retardation as
a part of time syndrome. Jonxis6 reported a
slight retardation in his cases; Albers and Wadman reported a progressive dementia;
and our Patient 1 had an IQ of about 80.
Hersov amid Rodnig1mt believe the present psychological evidence inadequate to
sup-Port the conclusion that a progressive
de-climie in intellect occurs in Hartnup disease.
On time contrary, recent observations,1l
sug-gest tilat patients with Hartnup disease
im-iirove clinically with age even without
treat-mnent. It is known, ilo\vever, that Permanent
nicotinamnide deficiency leads to mental
de-terioration, and time finding of 6 retarded
cilildiren among 16 patients stmggests such a
rd ationsimip. Nicotinamide timerapy may
possibly have prevented1 the intellectual
de-climme in the observed cases, thins masking
time natumral development of time disease.
Both our Patiemmts had anomalies of hair
growth. \Viletimer this imair anomaly has any-timing to do with time probable vitamin
de-ficiemicy is difficult to assess, bumt in severe
imutritional disturbances abnormal imair con-ditions are described.
The disease shows an irregular course
with exacerbations and remissions. Time cx-acerbations of the symptoms usually conic
in the spring or early summer nuonths.
No-tritional pellagra is also most common at thus time of time year.#{176} The exacerbations
seem to follow exposure to sunlight, and in
most cases time rash precedles tile other
symnp-toms. These facts point to a direct
relation-ship between the exposure to the sumnlight
and the symptoms of Hartnup disease, also
apart from the rasim. In three cases, how-ever, time exacerbations were preceded by febrile illnesses.’, 3,6
Nicotinamide and comnbined vitamin B
preparations have been tried as therapy, and there seems to be general agreement
about its effectivity on time skin lesiomis.
Usui-ally time rasim improves rapidly following
timerapy. Our impression after the first 13.
years of continuous treatment withm a
corn-bined vitamin B preparation is timat it also prevents new outbreaks and makes time skin
less pilotosensitive. Patient 1 in this report
had the typical rash every spring and
summ-mer since her first year, but following time
vitamin B timerapy timere lmas i)een no
reac-tion to sunlight. The effect of timerapy on time other symptoms is less obvioums, but our
un-pression is that the mental disturbances are
improved. Whetimer time cerebehlar ataxia and the otimer neurological symptoms are in-flumenced by timerapy is difficult to assess, because timey mnay subside ra)idlly witimout treatment. Vitamin B therapy imas no effect on time aminoacidumria.
Electroencephalograpimic investigations are reported in Hersov and Rodnigimt’s5
cases, and mild abnormalities were simown
in all. Albers and \Vadman’s patient also
showed EEG cimanges. In oumr Case 1 the EEG revealed a generalized dysrhytimmia
whmich improved definitely following several
mnontims of therapy. It is of interest to
per-form EEG examinations on all new cases to see if a common pattern camm be foumnd.
Time ultimate prognosis for patients with
Hartnup disease remains unknown, but recent observations indicate timat time
501 iHYI’FOIIIAN 5011 TRYPTA’IINE 5.011 INDOLEACETIC ACID
(5IliAA)
INDOLE INDICAN
XANTIIURENIC ACID
FOI1YIKY\UIIENINE KYNURENLNE 3-Oil KYNUIIENINE NICOTINIC ACID
3.011 ANTRANILIC ACID
36
Fir.. 7. The metabolism of tryptophan. therefore justified to reasstmre time patients
and! time 1)trentS that the outlook is good,
even timouigh some photosensitivity of time skimi may remain.
Nicotinic acid and imicotinamnide are
known to be comnponents of co-enzymes
playing a role in glycolysis. It is also known
that pehlagrins are easily subjected to
imypo-glycemic reactions.’#{176} Hickish reports an
“imnpaired” glucose tolerance test in his pa-tient. Our patient 2 suffered from a
hypo-glycemnic reaction during a 3-imour glucose
tolerance test. Time carboimydrate
metabo-lism shoumidl be fumrther investigated in
pa-tients vitim Flartnup disease during exacer-bations, as imypoglycemia may be a factor
in time patimogenesis of the unexplained
“fainting attacks.”
Time most constant and time
patimognomon-ic biocimemmiical alteration in Hartnuip
dis-ease is time aminoaciduria. This is
charac-teristic and has been termed the H-pattern.
Timis amimmoacidumria is of renal origin, as
miormal or low normal plasma amnino acid
ievelshl have been found. Timere is markedly increased excretion of alanine, serine, as-paragine, glutamine, vahine, time leucines,
plmenylalanine, tyrosine, tryptophan, and liistidine, btmt no excess of proline, which differentiates it from other types of
general-ized aminoaciduirias, stmcim as de
Tommi-Fan-coni syndrome. No other renal abnormali-ties have been detected.
In their original paper Baron et al.1 de-scribed an abnormal indole excretion as a
constant part of the Hartnup syndrome. Later the indole excretion has been found
to be less 13 but time cases
studied were without clinical symptoms at time time of investigations. The indican
ex-cretion Imas been grossly elevated in all ex-amined patients, and at least during periods with definite clinical symptoms indolic acids
are also excreted in 8The
chromato-graphic pattern of indole excretion varies somewhat, but seems to be fairly constant within one family. The indolic acids most
commonly found are indole acetic acid and indole acetyl glutamine, but also indole
lactic acid8 and indohe acryl glycine, which was very prominent in both our cases. The difference in indolic acid excretion may be due to age,” urinary pH,15 or diet.
The indoles and indohic acids are deg-radation products of tryptophan. Figumre 7
shows the many pathways by which
trypto-phan may be catabolized. Indole and
in-dican are formed in the intestine by micro-organisms. The indolic acids are probably products of the metabolism both of intes-tinal micro-organisms and body tissues. Nicotinic acid is an intermediate in the
ISI)OIEIYHt’VIC ACID INDOLELACTIC ACID (1LA)
TIYvrA\IINE INDOLEACET1C ACID INDOLEACETYL CLITAIINE
metabolismn of tryptophan, and in view of
the pellagra-iike symptoms of Hartnump
dis-ease, and time finding of abnormal indole
and indohic acid excretion, recent
investiga-tions into time primary lesion of the disease
imave been concerned with time metabolism
of time indoles. Tryptopiman loading tests
imave been a useful tool in these
investiga-tions.
In normal subjects, loading with 1-trypto-phan increases time excretion of IAA and to
a smaller extent ILA, and time peak of
ex-cretion is within 2 hours following the in-gestion of tryptophan.12 Kynurenine and kynurenic acid excretion is also increased.
In patients with Harthup disease there is
no increase in kynurenine excretion, while
time excretion of indican, IAA, and other
in-dolic acids is greatly increased and remains Imigim for at least 24 hours.12 In both our
cases loading withi l-tryptophan increased
time excretion of indican, IAA, IAcGIuNH2,
and IAcrylGly. Neomycin prior to time
tryp-topiman loading changed the excretion
pat-tern markedly. Indican, IAA, IAcG1uNH2,
amid IAcrylGly were excreted in definitely
smaller amounts, and we could thus con-firm time findings of Shaw
et al.’
that theaction of intestinal micro-organisms on
tryp-topiman before absorption is time probable
source of time urinary indolic acids in
Hart-nuip disease.
Baron Ct
al.
postumiated a block in thefor-mnation of nicotinic acid from tryptophan,
thus making time patients entirely
de-pendent upon time exogenous nicotinic acid
supply. Timey found little elevation of
urin-ary nicotinic acid excretion following
tryp-tophan administration in one patient. Mime
et
al.’
confirmed tlmis showing that patientswith Hartnup disease excreted about
one-tenth of time kynurenine excreted by normal
individuals following a similar tryptophman
load.
Time pathogenesis is still obscure,
al-timougim most investigators agree with the
original view of Baron
et a!.
timat timere isa diversion in tryptophan metabolism from
time kynurenic acid-nicotinic acid to time
in-dican pathway. This theory explains well
the pellagra-hike symptoms, buit not time aminoaciduria, and it imas been postulated that one or more of time abnormal
meta-bolites may lmave a toxic effect on the renal
tubules. Timere is not, however, any
experi-mental basis for this assumption. i\Iilne
et al.12 suggested timat a defective transport
of both 1-tryptophan and chl-tryptopiman
cx-ists in time disease and involves time cells of
the proximal renal tubules, jejunum, and
possibly the liver cells. A decrease in time
tryptopiman absorption from time intestine might increase time intestinal degradatiomm of
tryptopiman by micro-organisms and thins
cx-plain time abnormalities in indole excretion. Time cause of time cerebellar ataxia is even
less obvious. As time ataxia occurs in attacks,
it is probable that some external factors
may provoke thmem, and it imas also been
suggested timat time inclolic acids imave a
toxic effect. According to Jepson amid Spiro1 I
it is tmnhikely that IAA has stmchm
coimse-(ltlences. Both our latients excreted IAA, IAcG1uNH2, and IAcrylGly in excess, but
only time girl had ataxia.
Time inheritance pattern in Hartnup
dis-ease cannot be stated with certainty, but
time present information is consistemmt withm
an autosomal recessive transmission. It
would be important to be able to detect
Imeterozygoums carriers. p1 suggestedl
timat a tryptophan loading test migimt reveal
such cases in famnihies in wlmicim there is
Hartnup disease, but so far there have beemi no sucim reports. It is aim interestimmg pimmt
with our family that botim amm aumit amid
uncle Imave photosensitive skin. This was
also true with \Veyers’ and Bickel’s caseN
and simould be investigated in otimer cases, as
this may be a symptom of imeterozygosity.
Tryptopiman loading was mmormal in time
aunt, and both time uncle and aunt Imad
nor-mal amino acid and indole cimromatogrammms.
Time brotimer of oumr two patients silo\Vedl
time interesting finding of an indole
excre-tion pattern similar to timat of his two
af-fected siblings, and timis may be related to
time question of a carrier state. Withi time
amount of urine used and time present
pat-tern in normal individumals and doubt that the excessive excretion can l)e within
normal limits.
SUMMARY
Two cases of Hartnup disease in a Nor-wegian family with four cimildren from un-related parents are described. They have time typical peliagra-hike rash and the
H-pattern of aminoaciduria. Time urinary
in-dole excretion was markedly increased in both. Neomycin treatment prior to trypto-piman loading prevented time usumal increase
in indohic acids. A third sibling had the same urinary indole chromatogram but
neitimer clinical symptoms nor time H-pattern of aminoacidumria. In both proven cases
there were imair anomalies, in Case 1
patho-logical electroencephalographmic findings, amid in Case 2 a hypoglycemic reaction
dumr-ing a glucose tolerance test. On time basis of
a review of the literature and our own
cx-periences, it is concluded that nicotinamide or combined vitamin B preparations have
a definite value during acuite exacerbations,
and timat they probably improve the photo-sensitivity of time skin. Time vitamin therapy does not influence time abnormal excretion of amino acids.
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Acknowledgment
The authors are greatly indebted to Miss Anne
Brekke (clinical psychologist) who performed the
psychological studies, and to Miss Helene Lassen
